Enhanced endogenous glucose production (GP) is a major cause of fasting hyperglycemia in Diabetes Mellitus (DM). GP is normally inhibited by increased plasma levels of glucose and insulin. In fact, in response to acute increases in the plasma glucose concentration, GP is inhibited independently of hormonal signals in nondiabetic animals and humans. However, GP is increased in DM in the face of both hyperglycemia and hyperinsulinemia. The proposed experimental plan will first address the response of hepatic glucose fluxes to hyperglycemia per se in individuals with type 1 and type 2 DM as compared with normal individuals, in the presence of fixed hormonal conditions. Rates of hepatic glucose production and glucose cycling will be measured during somatostatin infusion with basal replacement of insulin and other hormones ("pancreatic clamp") in the presence of normoglycemia (plasma glucose ~ 90 mg/dl) and hyperglycemia (180 mg/dl). It is hypothesized that an impairment in the ability of hyperglycemia to enhance flux through glucokinase in the liver contributes to fasting hyperglycemia in DM. Thus, we will determine whether activation of glucokinase by small, catalytic amounts of fructose might restore glucose-induced suppression of GP in DM. Similar normoglycemic/hyperglycemic studies will be performed with infusion of fructose during the hyperglycemic phase, with measurement of rates of hepatic glucose production and glucose cycling. The vital role of the liver in the regulation of fasting plasma glucose levels suggests that defining the loss of normal hepatic regulation by hyperglycemia in DM would be valuable in developing targeted interventions. Specifically, enhancing glucokinase flux in the liver with small amounts of fructose may offer a simple and theoretically attractive means of improving glycemic control in Diabetes Mellitus.